The intentional deployment of biological agents to gain political and psychological advantage over a population must be taken seriously, as the anthrax scenario of fall 2001 served to confirm. To be prepared for future possible occurrences an organized study by the National Institute of Allergy and Infectious Diseases has identified certain pathogens, which are known, or substantially suspected, to have been investigated for bio-terrorism purposes. From this, priority areas were designated for counter-bioterrorism research: microbe biology, host response, vaccines, therapeutics, diagnostics, and research resources. This proposal will address the therapeutic need to combat two of the designated viruses: smallpox and viral hemorrhagic fevers (specifically, the filoviruses, Ebola and Marburg). There are currently no clinically approved drugs for these infections. Concurrent with the search for agents for treating smallpox will be the development of drugs for managing the side effects of smallpox vaccination (with vaccinia virus, an orthopoxvirus like smallpox), which could arise from mass immunization, if such was to occur. The therapeutic agent design to be considered is based on inhibition of the required N-7 methylation of the terminal guanosine in viral mRNA, which is necessary for successful translation. Inhibition can occur at the methyltransferase stage or by blocking the catabolism of S-adenosylhomocysteine (AdoHcy), the product of methyl transfer from S-adenosylmethionine (AdoMet), which inhibits the transferase by a feedback process. Both the orthopoxviruses (smallpox and vaccinia) and filoviruses are known to be vulnerable to this approach. The inhibitor design will be based on carbocyclic nucleosides, which are structures that lend themselves to controlling viral AdoMet/AdoHcy metabolism. These compounds will be synthesized following standard processes as well as following new, unique methods. Preliminary studies in the Project Leader's laboratory via this approach indicate that it will be successful. Virology collaborators are in place for the orthopoxvirus and filovirus assays and for assisting in determining the mechanism by which any active compounds are producing an observed antiviral effect. As an extension of this plan, collaborators have been included who will screen the library of newly synthesized compounds, which are targeted for anti-pox and -filo effectiveness, against other NIAID-identified viruses.